I received a query: Are there cases of famous scientists who did good
work but also made honest mistakes? Would I write something, as a historian
and philosopher of science, readable by a high school graduate, about several
such scientists? This paper is the response to that request.

Copyright by Lindley Darden 1998

The Nature of Scientific Inquiry

Professor Lindley Darden, Ph.D.

Committee on the History and Philosophy of Science

Department of Philosophy

University of Maryland, College Park

College Park, MD 20742

Introduction

Science is an error correcting process. Science thrives on open and
free debate about the merits of rival hypotheses. Sometimes many rivals
are considered before the best is found. It's the nature of scientific
inquiry that scientists publish hypotheses that may later be disproved
by new evidence and replaced by a better rival. Eventually some hypotheses
receive sufficient positive evidence. They become accepted as part of scientific
knowledge, with the proviso that even the best theories may be revised
in the light of new evidence.

Although science has improved its methods over the centuries, no method
exists to take data as input and produce true scientific theories as output.
The history of science shows that some scientists are better than others
at proposing plausible hypotheses that later prove to have the most evidence
in their favor. But even the best scientists have mixed records.

William Thomson, better known as Lord Kelvin, was one of the most famous
British physicists of the late nineteenth century. He was known for his
theoretical work on heat and for his practical work on the first trans-Atlantic
telegraph cable. However, his estimates of the young age of the earth,
based on the best physics of the late nineteenth century, turned out to
be way off the mark. His view was influential and geologists revised their
theories to accommodate a younger earth. Kelvin's estimate of the age of
the earth was significantly revised after the discovery of radioactivity
in the early twentieth century. Much longer time spans replaced Kelvin's
claims (Burchfield 1990).

The Italian physicist Enrico Fermi received the Nobel Prize in 1938
for two aspects of his work: the slow neutron technique and the "discovery"
of "transuranium elements." These two aspects suffered quite different
fates. The slow neutron technique proved useful in future work. However,
the "transuranium elements" that he thought he had detected were misinterpretations
of his experimental results. Instead of creating new elements, heavier
than uranium, he was splitting the uranium atom, thereby producing smaller,
lighter elements. Other physicists soon sorted out the mistake, leading
to the discovery of fission, the process used to make the atomic bomb (Weart
1983). Fermi accepted the reinterpretation of his results and went on to
contribute to further work leading to the use of fission in the atomic
bomb (Segre 1970).

The famous American chemist, Linus Pauling, helped to found the field
of structural chemistry with his important work on the nature of the chemical
bond, for which he received the Nobel Prize in 1954. His structural analysis
of proteins, showing what he called an "alpha helix structure," has proved
to be an important structural component of proteins. In contrast, Pauling's
model for another molecule-- DNA--was rapidly superseded. Pauling's three
strand model of the structure of DNA (deoxyribonucleic acid, the genetic
material), proposed in 1953, was bested in the same year by James Watson
and Francis Crick's two strand, double helix model. Pauling conceded his
mistake and corrected a small error in Watson and Crick's structure (Hager
1995).

The American James Watson and the Englishman Francis Crick received
the Nobel Prize in 1962 for their double helix model of DNA, built in Cambridge,
England, in 1953. After the discovery of the structure of the genetic material,
Crick went on to propose a "pretty, almost elegant" version of the genetic
code, called "the comma free code" (Crick 1988, p. 99). Horace Judson,
chronicling the history of this work, said of the comma-free code: "an
idea of Crick's that was the most elegant biological theory ever to be
proposed and proved wrong" (Judson 1996, p. 314). Crick attempted to test
his own, admittedly theoretical, hypothesis with genetic experiments, with
little success (Judson 1996). Marshall Nirenberg, using biochemical methods,
cracked the genetic code (Nirenberg 1968). Crick acknowledged the success
of the alternative experimental method and accepted the code that the biochemists
deciphered. His genetic own experiments later produced independent evidence
for some of the details (Crick 1988).

None of the errors of these famous scientists was due to fraud or misconduct.
Given the theories and evidence available to the scientist at the time,
the hypotheses that later failed were plausible. Publishing a plausible
hypothesis plays the important role of placing it in the marketplace of
scientific ideas. The person who conceives the hypothesis may not know
the best methods for testing it. One scientist may publish a hypothesis
and stimulate another scientist to design a crucial experiment to test
it. A single scientist may not be good at constructing all the plausible
alternative hypotheses that need to be considered. Publication may stimulate
another scientist to devise a plausible alternative. Or, publishing a plausible
hypothesis may save other scientists needless work on a problem and productively
focus the gathering of further evidence.

In an interview, Linus Pauling said:

A student once asked me, "Dr. Pauling, how do you go about having
good ideas?" and I answered: "You have a lot of ideas and you throw away
the bad ones." (Quoted in Buchanan 1985, p. 95)
This method works both for individual scientists and for the scientific
community. Individual scientists consider alternatives prior to publishing
and choose the one that is best supported by the evidence they have at
the time. Publication then allows the wider scientific community to continue
the same process (Darden 1991). Plausible ideas need to be published, subjected
to debate, challenged with new evidence. If a hypothesis turns out to be
bad, science throws it away. If it stands up in the face of further evidence,
then the scientist who first published it receives the credit. Science
as a whole benefits from timely publication and the scrutiny to which the
hypothesis is subjected (Hull 1988).

Scientific inquiry is an on-going process of error correcting--constructing
plausible hypotheses, generating as many plausible rivals as possible,
designing new experiments, correcting errors in hypotheses in the face
of anomalies. Cycles of discovery and testing and revision characterize
scientific change (Darden 1990; 1991).

Lord Kelvin and the Age of the Earth

William Thomson, Baron Kelvin of Largs (1824-1907), was knighted and
later named a baron in recognition of his many accomplishments in engineering
and science. He was instrumental in the engineering required for the first
successful trans-Atlantic telegraph cable and he was honored for his work
in thermodynamics and the theory of heat. He proposed a scale of absolute
temperature which today is still measured in degrees Kelvin. He published
over three hundred scientific papers and was regarded as one of the greatest
physicists of his time. But in one of the major scientific undertakings
of his life, Kelvin was in error. His calculations of the age of the earth
were made obsolete by the discovery of radioactivity. Kelvin had based
his mathematics on the earth's cooling from a molten mass, assuming only
the sun as a significant energy source. Radioactivity was unknown until
the very end of the nineteenth century; surprisingly, the earth was its
own source of additional heat.

Kelvin was the son of a Scottish professor of engineering and mathematics.
He graduated from Cambridge in 1845 and the next year became professor
of natural philosophy at the University of Glasgow. He remained there for
fifty-three years, becoming known as one of the greatest physicists of
that time. His work on heat and thermodynamics led him to question several
of the positions then held by geologists.

In order to understand the nineteenth century and prevailing views about
the sun, the earth and geology, we must remember that the existence of
radioactivity was not known, not even suspected, until 1896. Kelvin and
others puzzled over the world around them. Two questions were: What is
the source of the sun's heat? How old is the earth? These questions were
related because the earth was assumed to have cooled from a molten state
with only the sun for an additional energy source. What was the sun using
for an energy source? Kelvin was among those who even seriously considered
the collision with meteors as a source of fuel for the sun and as impact
energy for the earth. But calculations indicated that even the highest
estimates of meteors hitting the sun would only sustain it for a few thousand
years. And the impact of meteors could have only a minor effect upon the
rate of cooling of the earth (Burchfield 1990). Kelvin suggested that the
sun was slowly contracting and in that way producing heat (Thompson 1910,
p. 537).

By the middle of the nineteenth century, most scientists had, in practice,
abandoned Bishop Ussher's pronouncement that the earth had been created
in 4004 B.C. and therefore was about 6000 years old. The geologists pondering
the formation of the earth's features fell into two camps: the catastrophists
and the uniformitarians. According to the catastrophists, the earth's surface
had been shaped by a series of cataclysmic events: earthquakes, floods
(they were willing to concede Noah's flood as the last of these, to the
theologians) and volcanic eruptions. These events were assumed to have
been far more destructive than similar events in remembered time. The uniformitarians,
following the ideas of James Hutton and Charles Lyell, maintained that
no events in nature other than what we now observe were needed--only the
action of water, wind, occasional earthquakes and volcanoes, and an immense
amount of time. Uniformitarian reasoning assumed that geological time could
not actually be measured or calculated (Buchwald 1976, p. 383).

In 1859 Charles Darwin published On the Origin of Species in
which he suggested that a struggle for survival among varying organisms
was the mechanism for evolution. Darwin's theory of natural selection apparently
required thousands of generations and hundreds of millions of years as
a time span for the earth. Kelvin published several papers attacking the
uniformitarian position. Many have speculated that Kelvin was actually
opposing Darwin's theory but chose to challenge him indirectly, through
questioning the age of the earth and hence the supposed time available
for evolution to have taken place.

Beginning in 1862, and for thirty years after, Kelvin published papers
arguing that, according to his calculations of the rate of the earth's
cooling, the earth could not possibly be old enough for either Darwin's
evolution by natural selection or for the uniformitarian scenario for the
formation of the earth's features. The first of these papers was "On the
Age of the Sun's Heat" (Kelvin 1862a); Kelvin stated that the energy of
the sun is not inexhaustible, that it is coming from slight contraction
of the mass of the sun, that the sun formerly was hotter, that it would
have made the earth hotter than it is now, leading to more severe heat,
storms and floods, and so the catastrophists were more likely to be right
than the uniformitarians (Thompson 1910). Kelvin also included an opinion
that the sun had not been illuminating the earth for as long as 100 million
years and certainly not for 500 million years. In the second paper, "On
the Secular Cooling of the Earth" (Kelvin 1862b) he said that considerations
of temperatures beneath the earth's surface led him to calculate that the
earth was not less than 20 million years nor more that 400 million years
old. The uniformitarians, on the other hand, were considering possible
time spans as great as thirty billion years (Thompson 1910, p. 539). Kelvin
did not relent. In 1865 he presented a paper pointedly entitled "The Doctrine
of Uniformity in Geology Briefly Refuted" (Kelvin 1865). In this and in
an 1868 address to the Glasgow Geological Society, he reiterated that a
fundamental assumption of uniformitarianism was contrary to natural laws.
According to principles of thermodynamics, since the earth was a cooling
body, it could simply not have been at the present temperature and with
the present conditions for hundreds of millions of years. Over the next
thirty years, as Kelvin refined his calculations, his estimates of the
age of the earth went down, from 400 million years to 100 million to 50
million to 20-40 million years, in 1897 (Burchfield 1990, p. 43).

No one had any better ideas. Kelvin's reputation was impeccable and
his methods and calculations seemed above reproach. He used the best available
data and the current laws of physics. As Kelvin's estimates of the age
of the earth decreased, geological theories were less and less in agreement
with them.

What Kelvin lacked as he did his calculations was the key to unlocking
the puzzle of the earth's age--radioactivity. Radioactive elements within
the earth's crust decay; they generate heat as they do so. This additional
source of heat was unknown, even unsuspected, when Kelvin was making his
calculations. Becquerel discovered the existence of radioactivity in 1896.
In 1903 it was announced that radium is always hotter than its surroundings;
it steadily gives off heat (Burchfield 1990, p. 163). By now Kelvin was
in retirement but still reading widely. To him it seemed impossible that
the heat was coming from within the radium, or any other radioactive element;
that would be a violation of one of the natural laws, the law of conservation
of energy. Kelvin argued for some external energy source.

Ernest Rutherford discovered that the source of radioactivity is disintegration
of the atomic nucleus. As a radioactive element disintegrates it ejects
particles (called alpha rays, beta rays and gamma rays, all invisible to
the eye) and releases heat. Kelvin was not convinced but most other physicists
were; the experimental evidence was strong. In Rutherford's memoirs is
a humorous anecdote about Kelvin. In 1904 Rutherford was about to give
a speech on radioactivity in which he disagreed with Kelvin's estimates
of the age of the earth when he realized Kelvin was in the audience.

"I... realized I was in for trouble at the last part of the speech...
Then a sudden inspiration came and I said Lord Kelvin had limited the age
of the earth, provided no new source of heat was discovered. That
prophetic utterance refers to what we are now considering tonight, radium!
Behold! The old boy beamed upon me." (Burchfield 1990, p. 164)
Rutherford concluded this speech, before the Royal Society, with a forthright
statement of the new order of things.
"The discovery of the radio-active elements, in which their disintegration
liberate enormous amounts of energy, thus increases the possible limit
of the duration of life on this planet, and allows the time claimed by
the geologist and biologist for the process of evolution." (Burchfield
1990, p. 164)
Kelvin never published any acknowledgment that radioactivity was supplying
heat to the earth's crust and that thus his calculations of the age of
the earth were not accurate. Indeed, in 1906 and 1907 he published several
letters and papers denying that radium could be a source of heat within
the earth or the sun. However, another physicist, J. J. Thompson, related
in his own memoirs that "in private conversation Kelvin did concede that
his theories had been overthrown" (Burchfield 1990, p. 56, note 52).

Kelvin was regarded as one of the greatest physicists of the nineteenth
century. He received many awards and served a term as president of the
Royal Society of London, the most august group in British science. His
methods and calculations were admirable, but natural processes unknown
to him made his estimates of the age of the earth far from accurate. "Radioactive
dating...stretched the geological time scale by two orders of magnitude,
from...20 million years, past Darwin's 300 million years, to the immense
figure of three to five billion years" (Brush 1979, p. 148).

Enrico Fermi: "Transuranium" Elements, Slow Neutrons

Enrico Fermi (1901-1954) received the Nobel Prize in Physics in 1938
"for his demonstrations of the existence of new radioactive elements produced
by neutron irradiation and for his related discovery of nuclear reactions
brought about by slow neutrons" (Nobel Foundation).In his Nobel
lecture, Fermi described the years of experimentation with slow neutrons
and the bombarding of uranium; he named the new elements "ausonium" and
"hesperium" (Segre 1970, p. 217). The atomic number of uranium is 92; ausonium
and hesperium were thought to be numbers 93 and 94, respectively. Within
weeks of the Nobel ceremony, the discovery of nuclear fission was announced.
Uranium (92) had been split virtually in half; Fermi's supposed new elements
were actually familiar ones--barium (56) and a mix of krypton (36) and
other elements of similar weight (Hahn 1950, pp. 25-27). In contrast to
Fermi's misinterpretation of the uranium experiments, the discovery of
nuclear reactions brought about by slow neutrons proved fruitful in future
basic research, as well as for practical applications in the nuclear power
industry.

In 1926, prior to his Nobel prize-winning work, Fermi discovered "Fermi
statistics" governing the behavior of particles now called "Fermions,"
and leading to the Fermi-Thomas statistical model of the atom (Seitz 1955).
In 1927 he became the first holder of a chair in theoretical physics at
the University of Rome. Throughout the next decade he was instrumental
in the development of a modern school of physics there; a talented group
of young scientists assembled. Fermi gained a worldwide reputation as a
theoretical physicist, publishing in several different areas of physics.
In the 1930s, Fermi decided to redirect his research to nuclear physics,
leading to his work on both slow neutrons and transuranium elements.

In 1934 Frederic Joliot and Irene Joliet-Curie demonstrated that aluminum
could be made artificially radioactive by bombarding it with alpha particles
(two protons and two neutrons, the nucleus of a helium atom). What resulted
was a radioactive form of phosphorus which then decayed into silicon. The
suggestion was made that other particles could also be used for the bombardment
(Latil 1966, pp. 56-58).

Fermi decided to irradiate every chemical element in the periodic table
with neutrons, to see which would become radioactive. He and his group
started with hydrogen but had no luck until they got to fluorine. After
that, the radioactivity of many elements and the half-life of the radiation
were recorded. Late in 1934 came the observations that led to the discovery
of the effectiveness of slow neutrons. Repeated experiments with the same
element did not give the same results. Something strange was going on.
Fermi did experiments to exaggerate the unexplained variation; as part
of these experiments he deliberately placed a screen of paraffin wax between
the neutron source and the silver sample to be bombarded. The bombarding
neutrons were slowed down in their passage through the paraffin and were
better able to penetrate the silver. Apparently, substances rich in hydrogen,
such as paraffin or even water, could slow the neutrons (Latil 1966, pp.
58-65). Thus, Fermi had found a technique that he himself used for additional
basic research and that would prove fruitful for many subsequent applications.
The ability to control neutrons eventually made possible the use of atomic
energy for electric power plants.

In contrast to the slow neutron work, Fermi's interpretation of the
uranium bombardment experiments was soon discarded. In several papers in
1934, Fermi had suggested that neutron bombardment of uranium would produce
an element one atomic number higher than the 92 of uranium. This hypothesis
was plausible: other physicists had shown similar effects for other elements.
When elements lower in the periodic table are irradiated, the resulting
nucleus is a form of the next higher element. Fermi predicted that the
expected new element 93 would have certain chemical properties, based on
its expected location in the periodic table. His experimental results seemed
to agree with this prediction: among the mix of radioactive products of
the bombardment of uranium were some substances with the expected chemistry.
These substances were not any of the elements from lead (80) up to uranium
(92) in the periodic table. Because they were not below uranium in the
periodic table and because they were not uranium, Fermi thought that they
must be above uranium.

There was one voice of disagreement, to whom no one listened. Ida Naddock
sent Fermi and his group a copy of a paper she published in 1934, suggesting
that it was premature to talk of transuranium elements until tests were
done to exclude all of the known elements, not just those close to uranium.
Perhaps the nuclei were splitting into two parts to form elements of much
lower atomic number (Segre 1970, p. 76). This suggestion was apparently
taken as an appeal for rigor and thoroughness rather than as an alternate
hypothesis; it was ignored (Turner 1940, p. 2). During the next several
years, Fermi and others conducted many experiments to try to identify the
many radiation products. A single neutron bombardment of uranium 92 would
produce a mixture of several radioactive products having differing half-lives
and differing chemical properties. Most physicists accepted the hypothesis
that they were looking at transuranium elements. Some physicists had some
doubts but could not give any other interpretation of the experimental
results.

The Nobel ceremony honoring Fermi for slow neutrons and transuranium
elements was December 10, 1938. On December 22, Otto Hahn and Fritz Strassmann
sent their paper to the German journal Die Naturwissenschaften,
announcing the definite presence of barium (56) after irradiating uranium
(92) (Segre 1970, p. 99). Unlike the lower elements that absorbed the bombarding
neutrons, the uranium nucleus had split almost in half.

The hypothesis that the uranium nucleus would split into two or more
fragments simply had not occurred to most physicists. The theoreticians
knew that some theory permitted it (the liquid-drop model of the nucleus;
Weart 1983, p. 113) but didn't think it actually would happen, while the
experimentalists saw it and didn't believe it was what they were seeing,
because they thought it was not possible theoretically. In a letter to
Lise Meitner that December, Otto Hahn wrote, "Perhaps you can propose some
kind of fantastic explanation. We ourselves know that [uranium] cannot
really burst apart into barium" (Weart 1983, p. 112). The original manuscript
of the Naturwissenschaften paper included the phrase "contrary to
all previous laws of nuclear physics"; apparently upon becoming familiar
with the liquid-drop theory, Hahn changed the proofs of the article to
"contrary to all previous experience in nuclear physics" (Weart 1983, p.
113).

(In fact, Fermi's experiments had probably produced very small amounts
of transuranium elements. It is now known that bombardment of uranium is
how one makes neptunium (93) and plutonium (94). However, given Fermi's
techniques, the quantities would have been too minute to detect. What he
was measuring, but misinterpreting, were the products of fission, the splitting
of the uranium atom (Latil 1966, p. 82)).

After Fermi learned of the correct interpretation of his experiments
and accepted it, he went on to be a major player, using the correct interpretation,
in developing the atomic bomb. Fermi and his wife Laura and their two children
went to Stockholm in December of 1938 for the Nobel ceremony. From there
they proceeded to New York City without returning to Rome. Fermi and Laura
had decided that if he were to be awarded a Nobel Prize they would emigrate
to the United States immediately. The fascist anti-Semitic laws were becoming
increasingly repressive; Laura was Jewish (L. Fermi 1954).

Fermi became Professor of Physics at Columbia University. A few weeks
after his own arrival Fermi went down to the dock to welcome another new
immigrant, Niels Bohr. From Bohr he learned of the discovery of barium
in the irradiation products and therefore the discovery of nuclear fission
by O. Hahn and F. Strassmann. The news was circulating among scientists
in Europe but the journal article was still in press. Upon hearing from
Hahn of the presence of barium, Lise Meitner and her nephew Otto Frisch
had reasoned that the nucleus had split apart into two pieces whose charge
would still total that of uranium. They calculated the huge energy that
would be released. In January of 1939 they sent a paper to Nature;
to Meitner and Frisch we owe the word "fission" (Hahn 1950).

Fermi and many other physicists immediately recognized the possibility
of a chain reaction. When the uranium atom split, not all the neutrons
would become part of the barium and krypton. At least two neutrons were
always left over. If these neutrons could be made to collide with other
uranium atoms, instead of being absorbed by something in the surroundings,
each of those atoms would split and release two neutrons, and so
on: a self-sustaining nuclear reaction.

Fermi directed the completion of the first such self-sustaining atomic
pile on December 2, 1942, underneath the grandstand at Stagg Field at the
University of Chicago. In this and later as part of the group of scientists
at Los Alamos, he was a rare combination of theoretical physicist and experimentalist.
His efforts proved important to both the development of the atomic bomb
and the peaceful uses of nuclear power.

Linus Pauling: The Alpha Helix and The Triple Helix

Linus Pauling (1901-1994) received a Nobel Prize in Chemistry in 1954
"for his research into the nature of the chemical bond and its application
to the elucidation of the structure of complex substances" (Nobel Lectures,
1964, p. 425). Throughout his long career, Pauling applied his prodigious
talents to many problems in chemistry, with numerous successes and failures
(Hager 1995).

No straight forward method exists to determine the three-dimensional
arrangements of atoms in complex molecules. In the early twentieth century,
European and British physicists developed the technique of x-ray crystallography.
Molecules are x-rayed and the photographs, though complex, provide clues
as to the three dimensional structure. A. A. Noyes at the California Institute
of Technology saw the promise of this new technique for chemistry. When
Pauling arrived in 1922 at Cal Tech as a graduate student , x-ray crystallography
was the most important chemical research technique there (Hager 1995, p.
88). After receiving his Ph.D., Pauling remained at Cal Tech on the faculty.
In addition to learning x-ray crystallography, Pauling traveled in Europe
to learn about new developments in quantum physics. He pioneered the application
of new ideas about atoms from physics to chemistry. His book The Nature
of the Chemical Bond (1939) became a standard textbook (Hager 1995).
Pauling developed the method of combining evidence from x-ray data and
knowledge of chemical bond angles and distances to build plausible structural
models of molecules, which were then tested against further evidence. Because
the x-ray data alone were insufficient to show the structure of complex
molecules, model building and further testing proved a valuable method.

In the 1950s, Pauling applied his methods to large biological molecules--proteins
and DNA--with very different results. In 1950, Pauling and his colleague
Robert Corey published a paper in which they proposed a model for a structure
found in proteins, the alpha helix. In 1953, they published a proposed
structure for DNA, a triple helix. A helix is a spiral-like structure;
the alpha helix was a single helix; Pauling's proposed DNA structure had
three spirals. Additional evidence has ruled in favor of the alpha helix
model as a component in proteins but against the triple helix model of
DNA.

Pauling had hesitated to publish his alpha helix model of proteins for
two years after coming up with the idea (1948-1950), because the model
did not agree with one experimental result (technically: a strong spot
on the x-ray photographs that seemed to indicate a repeat in the helix
at 5.1 angstroms). Despite this one problem, additional evidence mounted
in favor of Pauling's alpha helix model. He published despite not having
an answer to the problem (Pauling and Corey 1950; Pauling et al. 1951).
Proteins are composed of about twenty different smaller molecules called
"amino acids." The primary structure of proteins is a linear chain of amino
acids. The alpha helix is an arrangement of the chain of amino acids into
a spiral-like pattern. The size and shape of the spiral was calculated,
partially from the x-ray data, and partially from bonds and angles conforming
to Pauling's chemical bonding theories.

Max Perutz was in a group of x-ray crystallographers at Cambridge University
in England, which was often in rivalry with Pauling's Cal Tech lab. When
Perutz read of Pauling's alpha helix, he immediately saw a way to test
Pauling's model. He took additional x-ray photographs and found new evidence
supporting the model. Publication, even in the face of some negative evidence,
allowed other scientists to devise new tests of the alpha helix (Olby 1994,
p. 293).

Later the problematic experimental result was explained away. It was
shown to be the result of additional coiling of more than one alpha helix
strand, a "coiled coil" (Crick 1988, p. 59). So, in retrospect, Pauling
made a good decision to publish the alpha helix, despite knowing of one
bit of negative evidence. That anomaly was later resolved without changing
the alpha helix. It is a judgment call by an individual scientist at a
particular time how to weight the importance of seemingly disconfirming
evidence in the face of mounting positive evidence. The clarity of hindsight
shows that Pauling made the right judgment about the alpha helix.

Mounting evidence was pointing to DNA as the molecule carrying the genetic
information. Chemically, DNA was known to consist of three types of molecules:
sugars, phosphates, and "bases." The sugars and phosphates are chemically
bonded in a chain called a "backbone." To the backbone are attached the
"bases," four similar but slightly different molecules, usually abbreviated
as the four letters A, T, G, C (for "adenine," "thymine," "guanine," and
"cytosine"). However, the number of backbones and their arrangements in
three dimensions was unknown. In 1951, a paper (Ronwin 1951) was published
in the Journal of the American Chemical Society proposing a structure
of DNA. When Pauling read Ronwin's paper, he immediately saw that it was
wrong and he worked a bit then, in 1951, on the structure of DNA (Hager
1995, p. 399). Pauling had been interested in components of nucleic acid
since 1933 and occasionally returned to the problem. He began model building
in earnest in 1952 after seeing new electron microscope photographs at
a seminar given at Cal Tech by a professor visiting from Berkeley (Pauling
1974). Pauling and Corey (1953) proposed a triple helix model of DNA, with
three sugar-phosphate backbones on the inside and the bases sticking out.
They based their "promising structure" on evidence from rather poor quality,
published x-ray photographs of DNA, in addition to other specific chemical
and structural evidence about DNA, and "general principles of molecular
structure." Pauling and Corey had tried to take better x-ray photographs
themselves, but the results were of poor quality (Pauling and Corey 1953,
p. 84-85).

When the group at Cambridge saw Pauling's proposal for a triple helix
model for DNA, they immediately saw its difficulties. Back in 1951, James
Watson and Francis Crick had built their own triple helix model of DNA
(explicitly using Pauling's model building techniques and his theory of
chemical bonding). That model was not published because colleagues told
them it was incorrect. Rosalind Franklin and Maurice Wilkins were x-ray
crystallographers at King's College in London working on DNA. Watson and
Crick invited them to view the 1951 scale model in Cambridge. Franklin
immediately saw a difficulty with the triple helix structure (Watson 1968).

Pauling's publication of his own triple helix model in 1953 spurred
Watson and Crick to new efforts to build a DNA model. Their productive
modeling building was guided by their own and Pauling's incorrect models,
which showed possibilities that would not work. The prior errors narrowed
the remaining possibilities. They also had the advantage of access to Franklin's
new x-rays photographs of DNA (Watson 1968). Their successful model building
resulted in their double helix model, with two sugar-phosphate backbones
on the outside of the helix (as Franklin had proposed) and the bases bonded
in the middle (the key new discovery) (Watson and Crick 1953; Olby 1994;
Judson 1996).

Pauling received an advance copy of Watson and Crick's 1953 manuscript.
Pauling wrote to his son Peter, who was working in Cambridge at the time:
"I think that it is fine that there are now two proposed structures for
nucleic acid [DNA], and I am looking forward to finding out what the decision
will be as to which is incorrect. Without a doubt the King's College data
will eliminate one or the other" (Quoted in Hager 1995, p. 427).

Pauling had not seen the new x-ray photographs. In 1953, Pauling visited
Cambridge on his way to a conference in Brussels. After seeing Franklin's
photograph and Watson and Crick's model, Pauling gracefully conceded defeat
(Hager 1995, pp. 427-428). At the conference he said: "Although it is only
two months since Professor Corey and I published our proposed structure
for nucleic acid, I think we must admit that it is probably wrong" (Pauling
at the Solvay Conference on proteins in 1953, quoted in Olby 1994, p. 422).
Although he attempted to refine his own model after returning to California,
Pauling soon gave it up as hopeless (Hager 1995, p. 428).

Pauling later corrected a small error in the Watson and Crick model
(Pauling and Corey 1956). Watson and Crick had proposed two chemical bonds
between two of the DNA bases (guanine and cytosine). Pauling proposed a
third. Watson (1968, p. 195), in a caption to a figure showing their original
view of two bonds, said: "The formation of a third hydrogen bond between
guanine and cytosine was considered, but rejected because a crystallographic
study of guanine hinted that it would be very weak. Now this conjecture
is known to be wrong. Three strong hydrogen bonds can be drawn between
guanine and cytosine." Pauling (1970, p. 1010) said: "This small refinement
of the double helix was immediately accepted."

The DNA story shows a common pattern in discovery: proposal of numerous
plausible alternatives hypotheses (either unpublished or published), mounting
evidence in favor of single one, acceptance of the correct one, further
refinements to improve it. Interestingly in this case, the publication
of incorrect models by others spurred both Pauling and Corey's as well
as Watson and Crick's work on the DNA model.

Francis Crick: The Double Helix and The Genetic Code

Francis Crick (b. 1916) shared the Nobel Prize in 1962 with James Watson
and Maurice Wilkins for their work on the structure of DNA. DNA is a large
molecule in the chromosomes of the cell that carries the genetic information,
in a coded form, for making the proteins in organisms, and thus, the genetic
characteristics of organisms. Determining the structure of DNA and then
deciphering the genetic code are among the most important achievements
of twentieth century biology. Crick participated in both. He and Watson
proposed the now-accepted double helix structure for DNA. However, the
genetic code that Crick proposed, though elegant, was not confirmed by
subsequent evidence.

In 1953, Watson and Crick (1953) determined the correct structure of
DNA, a double helix. It resembles a spiral staircase, with two sugar-phosphate
backbones forming the outer railings and four bases, joined in pairs across
the middle, to make the stairs. Watson and Crick relied on chemical knowledge
of the components of DNA, data from x-ray photographs of DNA taken by Maurice
Wilkins and Rosalind Franklin (who died before the Nobel Prize was awarded
in 1962), and the model-building techniques of Linus Pauling. One important
piece of chemical knowledge was supplied by Jerry Donohue, who had worked
with Pauling at Cal Tech but was visiting at Cambridge in 1953. The forms
of the bases in chemistry textbooks were incorrect; Donohue showed Watson
and Crick the correct chemical structures (Watson 1968).

The story of the discovery of the double helix model was told by Watson
in his delightful book The Double Helix (1968). The book graphically
portrays the many ideas they tried, and the failed models they considered,
prior to their successful model building. Watson's account leaves the reader
somewhat amazed that these fellows had succeeded in finding a successful
model where the famous Linus Pauling and the more experienced x-ray crystallographers
had failed. Watson was an American postdoctoral fellow visiting at Cambridge,
and Crick was a British physicist who had turned his attention to the study
of biological molecules but had yet to finish his Ph.D.

After the discovery of the double helix model of DNA in 1953, Crick
rapidly finished his Ph.D. in 1954, and turned his attention to other biological
problems, including the genetic code. As Watson and Crick saw, the problem
after discovering the structure of the genetic material was to understand
how it functioned. Although DNA is the genetic material, most of
the work in the cell is done by proteins. The genetic code specifies a
relation between DNA and proteins. The coding problem was to decipher how
the order of the bases along the DNA helix determines the order of amino
acids that make up proteins. Because there are four different bases in
DNA but twenty different amino acids in proteins, cracking the code meant
determining how many and which bases correspond to which amino acids. If
bases were taken two at a time, the sixteen possible combinations would
not be enough. So the minimal number of bases needed to code for one amino
acid appeared to be three.

Many different codes were proposed on theoretical grounds; some were
published and some circulated in manuscripts but were never published.
Some codes placed restrictions on which amino acids could be next to each
other in proteins. Such restrictions allowed Crick to use the known sequences
of proteins to test and eliminate some of the proposed codes (Judson 1996,
Part II).

In 1957, Crick, along with colleagues Griffith and Orgel, published
a paper in the Proceedings of the National Academy of Sciences (USA)
entitled: "Codes Without Commas." They stated the problem: "The problem
of how a sequence of four things [DNA bases]...can determine a sequence
of twenty things (amino acids) is known as the "coding" problem" (Crick,
Griffith and Orgel 1957, p. 416). They discussed theoretical and empirical
difficulties with previously proposed coding schemes, then opted for a
code in which three bases determine one amino acid. "This," they said,
"confronts us with two difficulties: (1) Since there are...64 different
triplets of four nucleotides, why are there not 64 kinds of amino acids?
(2) In reading the code, how does one know how to choose the groups of
three?...This second difficulty could be overcome by reading off from one
end of the string of letters [now known to be how the code is read], but
for reasons we shall explain later we consider an alternative method here"
(Crick, Griffith and Orgel 1957, p. 417). They then proposed a scheme for
combining the four bases in groups of three with certain restrictions so
that only twenty combinations were possible. Because this coding scheme
gave the "magic number" 20, the exact number of amino acids for which codes
were needed, they concluded that it may "perhaps be of biological significance"
(Crick, Griffith and Orgel 1957, p. 416). They also provided reasons, based
on chemistry, for the plausibility of this coding scheme.

Reflecting on Crick's work, Horace Judson in his history of this period
in molecular biology said:

"By 1966, he [Crick] had written two dozen papers related to the subject
[of protein synthesis and the coding problem]. Six at least were of great
and general importance. Two of those included experiments and were written
with collaborators. One more paper [the Crick, Griffith and Orgel paper
discussed above], of pleasing ingenuity, happened to be wrong: nature turned
out to be less elegant than Crick's imagination." (Judson 1996, p. 288)
Reflecting back on this work himself, Crick said:
"if we were to image that the correct triplets were marked by commas
(for example, ATC,CGA,TTC,...), how did the cell know exactly where to
put the commas? The obvious idea, that one stared at the beginning (whatever
that was) and went along three at a time, seemed too simple [this is indeed
how it happens], and I thought (quite wrongly) that there must be another
solution." (Crick 1988, p. 99)
Crick extolled the aesthetic properties of their comma free code: "Naturally
Orgel, Griffith, and I were excited by the idea of a comma-free code. It
seemed so pretty, almost elegant. You fed in the magic numbers 4 (the 4
bases) and 3 (the triplet) and out come the magic number 20, the number
of amino acids. Nevertheless I was hesitant. I realized we had no other
evidence for the code, other than the striking emergence of the number
twenty" (Crick 1988, pp. 99-100). They wrote an informal paper and circulated
it among colleagues for comments. Crick noted that in spite of his worries,
the new code attracted attention. After people began asking to quote the
unpublished paper, they decided to publish and did so in 1957. "An account
of it even appeared in a book for the general reader called The Coil
of Life written by Ruth Moore [a journalist], though this was not published
till 1961, by which time we had ceased to believe in the idea" (Crick 1988,
p. 100).

Crick himself, always more a theoretician than an experimenter, began
doing genetic experiments to try to obtain experimental evidence for the
code. These were difficult experiments. No direct method for sequencing
DNA was available at the time. Geneticists did not crack the code. Biochemists
did. Marshall Nirenberg and J. H. Matthaei (1961) at the National Institutes
of Health created a synthetic nucleic acid, put it into a experimental
system for synthesizing proteins, and determined experimentally the first
code for an amino acid (Nirenberg 1968). It was a possibility excluded
by Crick's comma-free code, showing that Crick's elegant proposal was wrong,
as Crick stated in his Nobel Lecture. "Comma-less triplet codes:
All such codes are unlikely, not only because of the genetic evidence but
also because of the results from the cell-free system" (Crick 1962, p.
211). Quickly the rest of the genetic code was deciphered by Nirenberg
and other biochemists (Judson 1996, Ch. 8). Indeed there is a start signal
and commas are not needed to separate the coding triplets. The idea that
Crick had considered and rejected is how nature does it. Nature's code
is less elegant than Crick's because some of the twenty amino acids are
coded for by more than one triplet, a messy result excluded by Crick's
comma-free code with its "magic number" of twenty.

Crick's genetic experiments, though they did not provide evidence for
this comma-free code or provide the first breakthrough in cracking the
code, did provide independent evidence for some aspects of the code. In
particular, the genetic experiments provided evidence that the code is
a triplet code, three bases code for one amino acid. Mutations showed different
behavior when three bases, rather than two or three, were deleted (Crick
1962, p. 107; Crick 1988; Judson 1996, p. 467).

Crick, reflecting back on lessons learned from his theoretical work
said:

"Theorists in biology should realize that it is...unlikely that they
will produce a good theory at their first attempt. It is amateurs who have
one big bright beautiful idea that they can never abandon. Professionals
know that they have to produce theory after theory before they are likely
to hit the jackpot. The very process of abandoning one theory for another
gives them a degree of critical detachment that is almost essential if
they are to succeed" (Crick 1988, p. 142).

Conclusion

In all four cases of errors by well-known and successful scientists,
their hypotheses were plausible at the time, given the evidence that they
had available and the theoretical framework within which they were working.
Further scientific work served to correct the mistakes.

It is a necessary part of scientific inquiry that alternative, plausible
hypotheses be considered (Lederberg 1965). Sometimes an individual scientist
constructs alternatives and does experiments to choose among them before
publishing anything. At other times, the published scientific record is
the forum for discussing competing alternatives. Subsequent published work
sorts things out (Darden 1991).

Science has developed a reward system of giving credit to the scientist
who publishes first, which ensures open and free discussion of ideas. Peer
review of scientific articles prior to publication serves as a check against
hasty publication of results that do not conform to the accepted standards
in the field. But peer review is not a guarantor of truth. No methods exist
to guarantee truth. Nonetheless, science, as it has developed over the
centuries, has improved its methods. As the philosopher of science Dudley
Shapere (1984) puts it: we learn how to learn as we learn.

Copyright by Lindley Darden 1998

Acknowledgments

Help from the following people is gratefully acknowledged: Spencer Weart
of the American Institute for Physics for information about Kelvin and
Fermi; the Niels Bohr Library of the American Institute for Physics for
materials; Stephen Brush for information about Kelvin; Gregory Morgan and
Bruce Buchanan for information about Pauling; Robert Olby for information
about Crick; Natalie Robert for her work as my undergraduate research assistant;
and Nancy Hall, as my graduate research assistant for her extensive work
on the Kelvin and Fermi sections.

References

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